This research project proposes a partnership between the drug research company Medivir AB (Sweden) and the nonprofit, nongovernmental organization, Population Council (US). The aim is to develop a novel combination microbicide containing two or more active pharmaceutical ingredients to block infection by HIV-1 and 2, hepatitis B virus (HBV) and herpes simplex virus-2 (HSV-2). Medivir AB will assay about 2000 NNRTI(s) from their exhaustive library of potential anti-virals for ability to bind to HIV and HBV retrotranscriptases. The plasmon resonance assay will be used to determine on and off binding rates using recombinant viral polymerases. Compounds with the best on/off binding rates will be analyzed by the PIs. The Population Council's Carraguard has demonstrated efficacy against HIV and other sexually transmitted pathogens in vitro and in animal studies. The Council will optimize Carraguard Based Antiviral formulation(s) (CBAVs) containing NNRTl(s) and anti-HSV compound(s) for use in a "cocktail" microbicide efficacious against a broadspectrum of STIs. CBAVs will be screened in the following regimens: a 3-stage regimen assessing stability;a 3-stage regimen assessing toxicity;and a 2-stage regimen assessing in vitro and in vivo pharmacokinetic profiles. Effectiveness against clinical isolates of HIV-1, with emphasis on subtype C viruses, and HIV-2 will be evaluated. Additionally, CBAVs will be compared to Carraguard in vitro against HBV and in the HSV-2/mouse system for efficacy against HSV-2. Our goals are to improve the formulation's efficacy against a broader range of sexually transmitted diseases (STDs) and increase its strength by adding anti-viral compounds that are active against HIV-1, HIV-2, HBV and HSV-2.